INB03 is a protein biologic that could have many beneficial effects in patients with cancer. Our initial focus is on its ability to inhibit proliferation and function of Myeloid-Derived Suppressor Cells (MDSC). By preventing the proliferation and function of MDSC, we believe patients will have a stronger immune response to cancer cells and may respond better to other cancer treatments including immunotherapy. Our approach includes a three-step process:
- Step 1 Inhibition of MDSC: MDSC proliferate in many patients with cancer. They migrate to the cancer cells and take up residence in the tumor microenvironment (TME). In the TME, MDSC secrete immunosuppressive cytokines that prevent the patient’s immune system from attacking the tumor and promote resistance to immunotherapy. The number of MDSC in the blood and TME predict severity of the cancer and resistance to immunotherapy. Experts agree that decreasing the number of MDSC may improve the response to immunotherapy such as checkpoint inhibitors and may improve the ability of the immune system to fight the cancer.
INB03 decreases the number and function of MDSC by preventing ligation of CD120a (TNFR1) that causes phosphorylation of STAT3, an intracellular pathway essential for MDSC proliferation and function. By stopping proliferation, the MDSC population collapses, causing a decrease in immunosuppressive factors that produce the shield protecting the tumor from the patient’s immune system. Without this immunosuppressive shield, the patient’s natural killer (NK) and T cells can attack the tumor, giving treatment with immunotherapies a better chance of being effective.
- Step 2 Promotion of NK/DC crosstalk: One role of NK cells is to help dendritic cells (DC) expand the immune response by facilitating immunologic crosstalk between the innate and adaptive immune system. High levels of soluble TNF promote conditions that prevents efficient immunologic crosstalk. When the system is working properly, NK/DC crosstalk allows for a more robust immune response.
- Step 3 Expansion of Immune Response: NK/DC crosstalk causes secretion of immune-regulatory cytokines that communicate with the adaptive immune system and promote anti-tumor immune responses. The NK cell/DC crosstalk and immune-regulatory signaling result in recruitment and expansion of the CD8+ cytotoxic T cell populations that attack and destroy the tumor.
In animal studies, those treated with INB03 had smaller and fewer tumors, resulting in increased survival.
We are currently conducting a Phase I trial with INB03 in patients with advanced solid tumors.
How does INB03 work?
INB03 is a novel, second-generation TNF inhibitor that works by a Dominant Negative technology. INB03 is a PEGylated protein therapeutic that is administered as a once-weekly subcutaneous injection similar to an insulin shot. INB03 is not an antibody. INB03 neutralizes soluble TNF without affecting any other parts of TNF biology, allowing for more precise targeting. INB03 is differentiated from first-generation, approved TNF inhibitors that are used to treat autoimmune disorders such as rheumatoid arthritis. These first-generation TNF inhibitors are contra-indicated in patients with cancer because they cause immunosuppression, a side effect that could worsen the cancer.